Chlorination of acetoacetamides

ABSTRACT

A process for the production of alpha-chloroacetoacetamides comprising the direct chlorination of acetoacetamides between 0* and 35*C, in a reaction medium consisting of a polar solvent and in the presence of an agent capable of causing enolization of the amide.

States Patent [191 Scharpt [111 3,852,351 Dec.3,1974

[ 1 CHLORINATION 0F ACETOACETAMIDES [75] Inventor: William G. Scharpt,Yardley, Pa.

[73] Assignee: FMC Corporation, New York, NY.

[22] Filed: Oct. 2, 1972 [21] Appl. No.: 294,458

[52] US. Cl 260/562 B, 260/561 K [51'] Int. Cl. C07c 103/00 [58] Field011 Search 260/561 K, 562 K, 562 B OTHER PUBLICATIONS Chem. Abstracts,74:141012Y.

Primary Examiner-Lewis Gotts Assistant ExaminerEthel G. Love ABSTRACT Aprocess for the production of alphachloroacetoacetamides comprising thedirect chlorination of acetoacetamides between 0 and 35C, in a reactionmedium consisting of a polar solvent and in the presence of an agentcapable of causing enolization of the amide.

5 Claims, N0 Drawings I CH3 (llNHcsHs and that this compound is usefulfor the control of certain plant diseases. Oxidation of this structureadds two oxygen atoms to the sulfur atom to produce the dioxide which isalso used to control plant diseases.

Known methods for preparing alphachloroacetoacetamides and for preparingalphachloroacetoacetic esters utilize sulfuryl chloride which in 1971cost $14.80 per pound mole. Normally, when chlorine ($2.84 per poundmole) is used as the chlorinating agent for acetoacetanalide, a mixedhalogenated product is obtained which surprisingly contains little or noalpha-chloro isomer. It is, therefore, desirable to have a process forthe direct chlorination of acetoacetamides, such as acetoacetanilide,with'chlorine to produce the corresponding alphachloroacetoacetamides.

In accordance with the present invention there is provided a process forthe reaction of acetoacetamides with chlorine to produce thecorresponding alphachloroacetoacetamides, in which acetoacetamides arechlorinated at temperatures between 0 and 35C in. a reaction mediumconsisting of a polar solvent, such as lower aliphatic alcohols of l to8 carbon atoms, in the presence of a compound which causes enolizationof the acetamides such as Lewis acids or chelates. Substantially,anhydrous conditions are necessary. An inert atmosphere, such asnitrogen, can be used to .facilitate maintenance of substantiallyanhydrous reaction conditions. Atmospheric pressure is generally used ashydrogen chloride is evolved. However, subatmospheric pressures can beused provided the overall temperature-pressure conditions do not causethe reaction media to boil and cool the media excessively.

I The chlorination reaction is exothermic, and thus the time isdependent upon the efficiency of the heat removal system as well as thestirring employed to maintain an equilibrium temperature in the reactionmixture. The acetoacetamides can be produced in situ in the reactionmedia by reaction of diketene with an appropriate amine prior to thechlorination reaction.

The chlorination reaction is as follows:

2 in which R can be hydrogen, alkyl or aryl and R can be hydrogen, alkylor aryl. An excess of chlorine can result in the production ofdichloroacetoacetamides and an insufficiency of chlorine would yieldmonochloroacetoacetamide mixed with unreacted acetoacetamide.

Acetoacetamides which can be chlorinated by the process of thisinvention include but are not limited to acetoacetanilide,acetoacet-meta-xylidide, acetoacetortho-anisidide,acetoacet-ortho-toluidide, and N, N- dimethylacetoacetamide.

Alcohols suitable as the reaction medium include lower aliphaticalcohols of l-8 carbon atoms such as propanol, 2-e thylhexanol,n-butanol, and so forth. lsopropanol was particularly valuable in thechlorination of acetoacetanalide where the a chloroacetoacetanilide wasdeposited in a form that could be isolated by filtration. The amount ofpolar solvent was varied between 300 and 1,000 milliliters per mole ofstarting material. The preferred concentration was 300 milliliters permole because of ease of isolation of product. The reaction mixturegenerally starts as a slurry of acetoacetamide which slowly dissolvesand gradually forms a slurry of chloroacetoacetamide. The reaction canproceed as a solution or as a slurry.

Use of toluene or an ethanol-heptane mixture as the reaction media forthe chlorination of acetoacetanalide resulted in diminished yields of ozchloroacetoacetanilide; chlorination of acetoacetanilide in aqueousmethanol did not produce alphachloroacetoacetanilide.

The reaction is conducted in the presence of a compound which causesenolization of the acetoacetamide. The use of either a Lewis acid or achelate enolizes the acetoacetamide. Useful Lewis acids include but arenot limited to ferric chloride, sulfuric acid, boron trifluorideetherate, titanium tetrachloride, zinc chloride, tin chloride (SnCl andagents that form chelates such as copper sulfate and ferrous sulfate andeven iron filings which form the iron halide in situ cause the desiredchlorination to occur. Concentrations of 0.4to 0.8 percent of Lewisacids or agents that form chelates, based on acetoacetamide, aregenerally used; lesser amounts of these materials can be used as canhigher amounts; of course, higher amounts can be economicallydisadvantgeous.

The process of the invention is typically run at temperatures betweenabout 0 and about 35C and preferably l5 to 25C. Temperatures below 0Ccan be used; temperatures above 35C but below both the decompositiontemperature of the acetoacetamide and boiling point of the solvent canbe used. Atmospheric pressure and a substantially anhydrous atmospheresuch as is provided by nitrogen, are useful reaction conditions.Substantially anhydrous reaction conditions are generally believed to besatisfactory as small. amounts of water interfere with the chlorination.The chlorine is typically added during about a 1 hour period and thereaction allowed to proceed for an additional 2 hours. The reaction isexothermic and since it is undesirable to have the reaction temperaturemuch above 35C the time is dependent upon the efficiency of the heatremoval system employed in the reaction equipment.

Thus, the'chlorine addition may va'ry between about 5% to 3 hoursdepending on the temperature. Efficient stirring is an important factorparticularly at low-concentrations of solvent per mole of the reactantsand efficient stirring helps to maintain an equilibrium temperature inthe reaction mixture.

The mechanism of the reaction is believed to be dependent on theformation of an enol tautomer of a l ,3- bis-carbo'nyl 'or a relatedcompound. Thus, it can be as sumed that wherever the ratio 'of enol isincreased, alpha-chlorination can be accomplished.

Examples of amides which fit this situation would be:

where: 1

R alkyl, haloalkyl, aryl,aralkyl, or substituted aryl R H or lower alkylof 1 to 4 carbon atoms R and/or R, H, alkyl, aryl, aralkyl, orsubstituted aryl R and R together form a heterocyclic group.

The following examples further illustrate this invention. In theexamples and throughout the specification all proportionsare by weightunless stated otherwise, and temperatures in degrees Centigrade.

1. In a 100 ml., 3-neck, round bottom flask fitted with a thermometer,magnetic stirrer, Dry-Ice condenser, and a dropping funnel topped with asecond Dry-Ice condenser was placed 8.85 g (0.05 moles) ofacetoacetanilide (commercial grade), m.p. 85, 20 ml. of anhydrousethanol, and 0.1 g of iron filings. The slurry was stirred andmaintained at 5-9 while 2.3 ml. (0.05 mole) of liquid chlorine was addedslowly during 70 minutes. The acetoacetanilide slowly dissolved, thenthe product slowly precipitated. After an additional 2 hours, themixture was filtered and the solid was dried in the desiccator to give6.5 g. (61.4 percent yield) of product, m.p. 128-l33. A portion wasrecrystallized from benzene, m.p. 135-7, and its infrared spectrum wasessentially identical with the spectrum of an au thentic sampleoA mixedmeltingpoint was not depressed. The mother liquor was concentrated togive a second crop of chloroacetoacetanilide, 2.3 g., total yield of 83percent.

2. The procedure of example I was repeated using 8.85 g.ofacetoacetanlide', 30 ml. of denatured, anhydrousethanol, 0.05 ofanhydrous ferric'chloride, and

-0.05 mole of chlorine to give a total of 8.2 g. of achloroacetoace'tanilide 78 percent yield.

3. The procedure of Example I was repeated using 8.85 g. ofacetoacetanilide, 120 ml. of 2-ethylhexanol, 0.05 g. 'of anhydrousmagnesium chloride, and 0.05

chloroacetoacetanilide, but mixed with a small amount of unreactedacetoacetanilide.

4. In a 500 ml. 3-neck, round bottom flask fitted with a thermometer,Dry-Ice condenser, magnetic stirrer, and a gas inlet tube was placed52.8 g. (0.3 mole) of acetoacetanilide, 150 ml. of anhydrous ethanol,and 0.2 g. of sulfuric acid. The slurry was stirred, maintained at 24,and treated with 15 g. (0.21 mole) of chlorine during 34 minutes. Afteran additional 2 hours, the mixture was filtered to give 10 g. ofproduct, m.p. l32-l40, and 17.3 g. as a second crop (yield 43 percentbased on acetoacetanilide, 62 percent based on C1).

5. In a 500 ml., 3-neck, round bottom flask, fitted with a thermometer,mechanical stirrer, Dry-Ice condenser, and inlet tube was placed 52.8 g.(0.3 mole) of acetoacetanilide, 0.2 g. of ferrous sulfate, and 90 ml. ofisopropanol. The slurry was stirred and maintained at 0 to 5 during theaddition .of 21 g. (0.3 mole) of chlorine. The addition took 46 minutesand the mixture was stirred an additional 2 hours, then filtered to give47.5

g. (76 percent yield) of crude product, m.p. 122-135.

6. In an apparatus as described in Example V above was placed 38.7 g.(0.3 mole) of N,N- dimethylacetoacetamide (from Pfaltz and Bauer Co.),ml. of isopropanol, and 0.2 g. of ferrous sulfate. The stirring reactionmixture was maintained at 2 l-24 during the addition, 45 minutes, of13.5 ml. (0.3 mole) of liquid chlorine. After stirring for,2 hourslonger the mixture was sparged with nitrogen, concentrated in vacuum andthen distilled through a 1 ft. Vigreux column to give a forerun of 9.3g., b.p. 76-80/0.5 mm., 17.7 g. of product, b.p. 8.l83l0.5-0.7 mm., and3.9 g. of afterrun, b.p. 845/0.7 mm. Nmr spectra confirmed thestructure, including alpha substitutions. Analysis: found 21.] percentchlorine as compared with 21.2 percent theoretical.

What is claimed is: a

1. A process for the production of alphachloroacetoacetamides comprisingthe direct chlorination with chlorine of acetoacetamides between 0 and35C, in a reaction medium consisting of a polar solvent and in thepresence of a Lewis acid capable of causing enolization of the amide.

2. The process of claim 1 in which the acetoacetamide is anacetoacetanilide.

3. The process of claim I in which the a Lewis acid causing enolizationis present in amounts of 0.4 to 0.8 percent by weight based on theacetoacetamide.

4.- The process of claim 1 in which the polar solvent is selected fromthe group consisting of ethanol, npropanoL'isopropanol, n-butanol,isobutanol, and 2- ethylhexanol.

5. The process of claim 1 in'which the Lewis acid is selected from thegroupconsisting of iron chloride, sulfuric acid, copper sulfate, ferroussulfate, and magnesium chloride.

1. A PROCESS FOR THE PRODUCTION OF ALPHACHLOROACETOACETAMIDES COMPRISINGTHE DIRECT CHLORINATION WITH CHLORINE OF ACETOACETAMIDES BETWEEN 0* AND35:C, IN A REACTION MEDIUM CONSISTING OF A POLAR SOLVENT AND IN THEPRESENCE OF A LEWIS ACID CAPABLE OF CAUSING ENOLIZATION OF THE AMIDE. 2.The process of claim 1 in which the acetoacetamide is anacetoacetanilide.
 3. The process of claim 1 in which the a Lewis acidcausing enolization is present in amounts of 0.4 to 0.8 percent byweight based on the acetoacetamide.
 4. The process of claim 1 in whichthe polar solvent is selected from the group consisting of ethanol,n-propanol, isopropanol, n-butanol, isobutanol, and 2-ethylhexanol. 5.The process of claim 1 in which the Lewis acid is selected from thegroup consisting of iron chloride, sulfuric acid, copper sulfate,ferrous sulfate, and magnesium chloride.